Holmes Michael V, Exeter Holly J, Folkersen Lasse, Nelson Christopher P, Guardiola Montse, Cooper Jackie A, Sofat Reecha, Boekholdt S Matthijs, Khaw Kay-Tee, Li Ka-Wah, Smith Andrew J P, Van't Hooft Ferdinand, Eriksson Per, Franco-Cereceda Anders, Asselbergs Folkert W, Boer Jolanda M A, Onland-Moret N Charlotte, Hofker Marten, Erdmann Jeanette, Kivimaki Mika, Kumari Meena, Reiner Alex P, Keating Brendan J, Humphries Steve E, Hingorani Aroon D, Mallat Ziad, Samani Nilesh J, Talmud Philippa J
Circ Cardiovasc Genet. 2014 Apr;7(2):144-50. doi: 10.1161/CIRCGENETICS.113.000271. Epub 2014 Feb 21.
Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.
Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20).
This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.
分泌型磷脂酶A2（sPLA2）酶被认为在动脉粥样硬化中起作用。sPLA2活性包括几种sPLA2同工酶，其中包括sPLA2-V。尽管观察性研究表明sPLA2活性升高与冠心病之间存在密切关联，但目前尚无检测sPLA2-V水平的方法，且将sPLA2-V同工型与动脉粥样硬化进展联系起来的唯一证据来自动物研究。在缺乏直接定量sPLA2-V水平的检测方法的情况下，我们采用一种新颖的、改良的孟德尔随机化方法，利用PLA2G5 mRNA水平来研究sPLA2-V在冠心病（CHD）发病机制中假定的因果作用。
利用主动脉病理学高级研究的数据，我们确定PLA2G5中的单核苷酸多态性与PLA2G5 mRNA表达水平关联最强，以此作为sPLA2-V水平的替代指标。我们在4项前瞻性研究和14项病例对照研究（共27230例事件和70500例对照）中测试了该单核苷酸多态性与sPLA2活性及冠心病事件的关联。rs525380C>A与PLA2G5 mRNA表达关联最强（P = 5.1×10⁻⁶）。rs525380C>A与血浆sPLA2活性无关联（每个rs525380 A等位基因的sPLA2活性几何平均数差异为0.4%（95%置信区间[-0.9%，1.6%]；P = 0.56）。在荟萃分析中，每个A等位基因的冠心病优势比为1.02（95%置信区间[0.99，1.04]；P = 0.20）。
这种用于改良孟德尔随机化分析的单核苷酸多态性选择新方法显示，rs525380（PLA2G5表达的主要单核苷酸多态性，sPLA2-V水平的替代指标）与冠心病事件之间无关联。证据不支持sPLA2-V在冠心病中起因果作用。
